DESCRIPTION: HIV-1 causes a persistent infection due to long-lived reservoirs of latently infected cells that present a barrier to achieving a cure. There are active efforts ongoing to eliminate the latently infected cells by using drugs that antagonize latency and activate viral gene expression. To date, the antagonists that have been identified tend to reactivate viral gene expression without efficiently killing the infected cells and clearing the reservoirs. Therefore, i may be necessary to develop immunotherapeutic approaches to ultimately clear the virus and cure disease. Cytotoxic T lymphocytes, which can recognize actively infected cells may aid in the clearance of reservoirs treated with latency antagonists. However, CTLs are limited in the extent to which they can effectively clear infection. Our long-term goal is to understand how to enable the immune response to more effectively recognize and eradicate latently infected cells that have been treated with latency antagonists. The overall objective of this application, which is the next step toward attainment of our long-term goal, is to identify compounds that maximize viral antigen presentation in HIV-infected cells. We hypothesize that while CTLs have activity against latently infected cells that have been induced to express HIV-1 genes, HIV-1 Nef, which down modulates MHC-I, limits the extent to which induced cells can be killed. Preliminary studies indicate that Nef inhibitors found in natural product extracts can reverse the effects of Nef and sensitize infected cells to CTL killing. These studies have led to the hypothesis that combination therapy with latency antagonists plus Nef inhibitors could act synergistically to clear reservoirs. The R21 phase of this proposal aims to complete the identification of inhibitory factors in high priority natural product extracts that contain anti-Nef activity. Upon successful completion of the R21 phase, The R33 phase will involve (1) determining the mechanism by which each factor inhibits Nef-mediated MHC-1 down modulation and (2) conducting lead compound optimization to improve the pharmaceutical properties and identify a leading drug candidate for development.